Despite significant advances in the treatment of asthma, optimal clinical therapy for patients with this increasingly common and potentially debilitating disease is still in flux. The first trial we propose for the Asthma Clinical Research Network (ACRN) emerges from expert-based guidelines recommending that individuals with mild-moderate persistent asthma symptoms, who comprise about 50% of patients requiring chronic asthma therapy, should be treated with controller agents such as inhaled corticosteroids (ICS). However, this may lead to over-treatment of many individuals who do not require such therapy. Data from a completed ACRN trial suggest that more than 60% of patients whose symptoms were controlled with continuous ICS did not experience exacerbations when discontinuing this medication. Our retrospective analysis of this trial suggests that changes in sputum eosinophils may identify 80% of the patients who can successfully discontinue inhaled corticosteroids. If confirmed, such a tool could prevent unnecessary treatment for a large cohort of asthmatics and result in an estimated $2 billion of savings per year. It could also identify patients requiring further therapy. We propose a double blind, placebo-controlled study to test this hypothesis. Our second trial focuses on patients with more severe disease, who account for a disproportionate amount of asthma-related morbidity. For patients whose symptoms persist in spite of treatment with ICS and a long-acting -agonist, alternatives are needed to the current recommendation of treatment with higher doses of ICS. Newer agents, such as leukotriene modifiers, may be beneficial for such patients. We will examine the effect of adding a leukotriene modifier to ICS and a long-acting -agonist vs. increasing the dosage of ICS with continuation of a long-acting -agonist among patients with moderate to severe asthma. Both trials will use asthma deteriorations as the primary outcome. In the second trial, we will also examine if the response to ICS therapy is associated with haplotypic variations in the gene coding for the glucocorticoid receptor and if the response to leukotriene modifiers is associated with polymorphisms of the LTC4 synthase promoter. This latter analysis may permit us to individualize therapy and therefore maximize benefit, decrease toxicity, and decrease cost.